POS0038 GENOMICS OF JAK-STAT SIGNALING IN VENOUS THROMBOEMBOLISM
Authors: S. Haysen, A. L. L. Nielsen, P. Qvist, T. W. Kragstrup
Journal: Annals of the Rheumatic Diseases (2022)

Background Janus kinase inhibitors (JAKi) have been associated with an increased risk of venous thromboembolism (VTE) [1] . VTE comprises deep vein thrombosis and pulmonary embolism and is associated with complications such as recurrent VTE, post thrombotic syndrome, pulmonary hypertension, and death. These concerns limit the use of JAKi-based therapy. To improve risk stratification and drug development, it is crucial to understand the possible implication of dysregulated JAK-signal transducers and activators of transcription (STAT) signaling in the pathogenesis of VTE. Objectives The objective of this study is to clarify the putative genomic vulnerability to dysregulated JAK-STAT signaling in VTE. Methods We are systematically mine and analyze large-scale genomic datasets generated from studies comparing VTE patients with healthy controls. Using VTE genome-wide associated (GWA) summary statistics we evaluate the representation of genes encoding the JAK-STAT pathway (KEGG hsa04630) in associated loci and assess their association to VTE. Further, we examine the genetic VTE risk burden in the chromatin interactome of STAT family transcription factors (TFs). We extract available STAT family (STAT1-3) TF binding site (TFBS) consensus DNA motifs (JASPAR database) and assess the association of genes containing STAT family TFBS within their promotor sequence (TSS -2000bp) to VTE. Through mining of deposited OMICs data from VTE patients, we examine molecular characteristics related to JAK-STAT signaling, including potential enrichment of STAT family TFBSs among query promoter sequences of differently expressed genes (DEGs). Results We do not observe a significant overrepresentation of JAK-STAT genes (n total =162) among genes annotated to VTE significant GWA loci (n total =147, p=0.48). Similarly, the JAK-STAT gene set show no cumulative association to VTE (p=0.98). Applying the same gene set association approach to the STAT target gene sets (n total =4570) does not reveal significant association between VTE and STAT1 (n overlap =10, p=0.47), STAT1:STAT2 heterodimer (n overlap =18, p=0.17) and STAT3 (n overlap =6, p=0.20) target gene sets. At the functional molecular level, we do not see any significant overlap between molecules acting in the JAK-STAT pathway and DEGs (n total =507, p=0.06) or differentially abundant proteins (DAPs; n total =35, p=0.57). However, we observe a significant overlap between downregulated DEGs (n total =362) and the STAT1:STAT2 heterodimer target gene set (n total = 2155, n overlap =48, p&lt;0.0001) including downregulation of IL-27RA and CCND3 (Figure 1). Supporting the biological relevance of this finding, we find a weak but statistically significant enrichment of STAT1 TFBS motifs in the promotor sequence of downregulated DEGs compared to non-DEGs (p=0.02). Figure 1. Overlap between STAT1:STAT2 heterodimer gene set and differently expressed genes (DEGs) in venous thromboembolism (VTE) Conclusion Here, we provide a coherent approach to assess the genomic basis for the reported association between JAKi treatment and VTE. Our preliminary data suggest that genes under transcriptional control of STAT family TFs may be dysregulated in VTE patients. It is conceivable, that the genomic actions of JAKi is overlapping with the molecular risk profile of VTE. CCND3 is especially interesting because VTE occurs in up to 10% of patients treated with cyclin-dependent kinase inhibitors such as Palbociclib [2] . Obviously, genomic data mining alone cannot guide medical decision making concerning the use of JAKi. However, our results provide a basis for further investigation of adverse events seen with JAKi. References [1]Charles-Schoeman, C., et al., The Risk of Venous Thromboembolic Events in Patients with RA Aged ≥ 50 Years with ≥ 1 Cardiovascular Risk Factor: Results from a Phase 3b/4 Randomized Safety Study of Tofacitinib vs TNF Inhibitors . Arthritis Rheumatol, 2021; 73 (suppl 10). [2]West, M.T., et al., CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real-world practice. Eur J Haematol, 2021. 106(5): p. 634-642. Disclosure of Interests Stine Haysen: None declared, Ane Langkilde-Lauesen Nielsen: None declared, Per Qvist: None declared, Tue Wenzel Kragstrup Speakers bureau: Speaking fees from Pfizer, Bristol-Myers Squibb, Eli Lilly, Novartis, UCB, and Abbvie., Consultant of: Consultancy fees from Bristol-Myers Squibb and Gilead., Grant/research support from: Research grants from Gilead., Employee of: Co-founder and clinical developer in iBio tech ApS.